Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey

A multicenter retrospective analysis was performed to estimate the frequency of thrombosis and hemorrhage after surgical procedures in patients with polycythemia vera (PV) and patients with essential thrombocythemia (ET). Data from 105 patients with PV and 150 patients with ET were analyzed, for a total of 311 surgical interventions. An emergency procedure was performed in 25 (8.1%) patients; 194 surgeries were done under general anesthesia, and 21 (23%) of 91 abdominal interventions were done under laparoscopy; 155 (50.1%) were major surgeries. Subcutaneous heparin was administered in 169 (54.3%) of 311 cases and antiplatelet therapy in 48 (15.4%) of 311 case interventions. One hundred eighty-eight (74%) of 255 patients were on cytoreductive therapy before surgery. No events were observed in 259 (83.2%) of 311 procedures during 3 months of follow-up; there were 12 arterial and 12 venous thrombotic events, 23 major and 7 minor hemorrhages, and 5 deaths. Arterial thromboses were more frequent in ET (5.3% vs 1.5%; P=.08), venous events were more frequent in PV (7.7% vs 1.1%; P=.002). There was not a correlation between bleeding episodes and the type of diagnosis, use of antithrombotic prophylaxis, or type of surgery. A high proportion of PV and ET surgeries was complicated by vascular occlusion (7.7%) or by a major hemorrhage (7.3%). Prospective investigations analyzing the optimal prophylaxis in these patients are suggested.     

CALM supports clathrin-coated vesicle completion upon membrane tension increase

The most represented components of clathrin-coated vesicles (CCVs) are clathrin triskelia and the adaptors clathrin assembly lymphoid myeloid leukemia protein (CALM) and the heterotetrameric complex AP2. Investigation of the dynamics of AP180-amino-terminal-homology (ANTH) recruitment during CCV formation has been hampered by CALM toxicity upon overexpression. We used knock-in gene editing to express a C-terminal–attached fluorescent version of CALM, while preserving its endogenous expression levels, and cutting-edge live-cell microscopy approaches to study CALM recruitment at forming CCVs. Our results demonstrate that CALM promotes vesicle completion upon membrane tension increase as a function of the amount of this adaptor present. Since the expression of adaptors, including CALM, differs among cells, our data support a model in which the efficiency of clathrin-mediated endocytosis is tissue specific and explain why CALM is essential during embryogenesis and red blood cell development.

Clathrin-mediated endocytosis (CME) controls multiple physiological activities in eukaryotic cells, including internalization of nutrients, receptors, and other membrane components. Endocytic clathrin-coated vesicles (CCVs) form by the recruitment of clathrin triskelia, adaptors, and other accessory proteins at specific plasma membrane sites (1). Biochemical experiments complemented by live-cell microscopy have allowed identification of several phases of CCV formation: initiation, growth/maturation, and completion (2). The initiation of “canonical” CCVs is defined by the coordinated recruitment of one triskelion and two heterotetrameric adaptor protein complexes 2 (AP2) at the plasma membrane (3). The majority of these nascent structures abort while a fraction can commit and grow further (4, 5). During the growth phase, the membrane invagination increases as more triskelia and adaptors are incorporated into the coat (6). Mass spectrometry analysis has shown that the AP2 and clathrin assembly lymphoid myeloid leukemia protein (CALM), also named Phosphatidylinositol-binding clathrin assembly protein (PICALM), are, together with clathrin, the most abundant protein components of CCVs (7, 8). While AP2 is a tetrameric adaptor (1), CALM is a single peptide chain that contains at its N terminus the AP180-amino-terminal-homology (ANTH) domain (9). The ANTH domain mediates CALM binding to phosphoinositides on the plasma membrane and to SNAREs that control the fusion of vesicles with specific acceptor membranes (10). CALM’s C terminus is unstructured and comprises binding motifs for clathrin, AP2, and EPS15 (11). Moreover, CALM is a driver of membrane curvature formation (12), which is critical for the construction of a CCV. Membrane curvature can be achieved only by overcoming local plasma membrane tension (13–16) that, together with the availability of CME components (17), determines the heterogeneity of clathrin structures at the membrane surface. We hypothesized that CALM recruitment can support the formation of CCVs even under mechanically stringent conditions, such as increased membrane tension. To test this, we used quantitative live-cell microscopy to study the recruitment of CALM to forming CCVs. Since CALM overexpression has dominant negative effects on intracellular clathrin distribution and CCV formation (18–20), we used gene editing to introduce protein tags at the C-terminal end of CALM so as to not perturb the N-terminal activity of CALM and to maintain its endogenous levels. Our results show that CALM functions as a major determinant of CCV formation upon membrane tension increase. Since CALM is differentially expressed among tissues, our results demonstrate that competence in CME is tissue specific and provide mechanistic explanation why CALM depletion strongly affects embryo development, red blood cell differentiation (21), and CALM polymorphisms are associated with Alzheimer''s disease (22), with minor effects in other systems.     

Initial experience with the disarticulated (one-half) palmaz-schatz stent: A technical report

We developed an alternative method to stent suitable lesions located in anatomical settings considered to be too complex for regular Palmaz-Schatz stent placement. This method consists of using a disarticulated (one-half) Palmaz-Schatz stent. Eight patients underwent stenting utilizing this method. The left anterior descending was stented in five patients, the right coronary artery in one patient, the proximal and mid shaft of a vein graft in one patient, and a protected left main coronary artery in one patient. In all patients the stents were placed in addition to full stents. In four patients, 1_1/2 stents were placed; two patients had 2_1/2 stents; one patient had 3_1/2 stents and the last patient had a total of 5 stents placed (1 full stent and 8 half stents). One patient had 8 disarticulated stents placed. All half stents prepared for delivery were successfully deployed to the pre-designated angiographic site without complication.     

Nizatidine and Ranitidine in the Short-Term Treatment of Duodenal Ulcer: A Cooperative Double-Blind Study of Once-Daily Bedtime Administration

The aim of the present study was to assess the clinical efficacy and safety of a new H2-antagonist, nizatidine (N), administered as a single bedtime dose of 300 mg, compared with ranitidine (R) at the same dosage, in the short-term treatment of duodenal ulcer. One hundred forty one patients were included in the study: 70 were treated with N and 71 with R. During the study, three patients were withdrawn for unwanted effects not related to the treatment, and therefore, 69 patients per group were studied. After 4 wk of treatment, 58 patients treated with N (84.1%) and 55 in the group treated with R (77.5%), showed complete endoscopic ulcer healing (p greater than 0.5). The corresponding figure after 8 wk of therapy was 64 (94.2%) and 65 (94.2%) (p greater than 0.5). A similar effect on pain relief was observed: 42% of patients in both groups became asymptomatic after 4 wk. After 8 wk, the percentage rose to 84.2% in the group treated with N and 87.0% in the R group (p greater than 0.5). In both groups, only minor side effects occurred, not requiring drug discontinuation. These data show that nizatidine in a single bedtime dose of 300 mg is as effective and safe as ranitidine at the same dosage, and represents therefore a valid alternative to the usual H2-antagonists.     

Heterogeneity of hereditary methaemoglobinaemia: a study of 4 Cuban families with NADH-Methaemoglobin reductase deficiency including a new variant (Santiago de Cuba variant)

NADH-methaemoglobin reductase deficiency has been found in 4 Cuban families; 3 subjects carried the mild form of the deficiency while in 2 sibs of the fourth family the deficiency was associated with neurological involvement. The parents in this family were consanguinous and the sibs were shown to be homozygous for a new fast electrophoretic variant. It was named Diaphorase Santiago de Cuba.     

Factor XI gene mutations in factor XI deficient patients of the Czech Republic

Factor XI (FXI) deficiency is an autosomal inherited coagulation disorder characterized by bleeding symptoms mainly associated with injury or surgery. Although most of the FXI gene mutations in Ashkenazi Jews are represented by the Glu117stop or Phe283Leu mutations, considerable genetic heterogeneity has been reported in other populations. We report here the genotypic characterization of four families with severe inherited FXI deficiency from the Czech Republic. Seven different gene mutations (three novel) were identified, thus, excluding the existence of a major founder effect in this population. Interestingly, both Glu117stop and Phe283Leu were detected once, further demonstrating the occurrence of these mutations also outside the Jewish populations. In conclusion, we confirm that FXI deficiency in non-Jewish populations is because of different gene mutations; however, the presence of the Glu117stop and Phe283Leu mutations suggests that genetic testing in FXI-deficient patients can start with these two point mutations.     

Does the specific intravascular ultrasound criterion used to optimize stent expansion have an impact on the probability of stent restenosis?

Intravascular ultrasound (IVUS) imaging has been used to optimize stent implantation in coronary arteries, but the criteria used were chosen on an empiric basis. The aim of this study was to determine whether any of these criteria have an independent role in predicting the probability of freedom from restenosis. The study population consisted of 425 patients (496 lesions) who underwent angiographically successful IVUS-guided stenting. Five IVUS criteria were studied: (1) intrastent minimal lumen cross-sectional area (ISMLCSA) > or =9 mm2; (2) ISMLCSA (> or =9 mm2 and > or =80% of average reference lumen cross-sectional area [CSA]); (3) ISMLCSA > or =90% of average reference lumen CSA; (4) ISMLCSA > or =90% of distal reference lumen CSA; and (5) ISMLCSA > or =55% of average reference vessel CSA. These criteria were met in 33%, 29%, 68%, 82%, and 69% of lesions, respectively. Angiographic follow-up was performed in 335 of 421 eligible patients (80%) at 5.3 +/- 2.7 months. An absolute ISMLCSA > or =9 mm2 was associated with the lowest restenosis, but this criterion was primarily achieved in large vessels. The only criterion that was associated with higher probability of freedom from restenosis independently from vessel size was an ISMLCSA > or =55% of average reference vessel CSA. Therefore, when IVUS is used to guide stent implantation an effort should be made to achieve the largest lumen safely possible. An ISMLCSA > or =55% of the average reference vessel CSA seems to be the most appropriate criterion in terms of frequency of achievement and in terms of increasing the probability of freedom from restenosis.